Alpha-amino alcohols find wide use in industry, e.g. as starting materials and intermediates in the production of tensides, pestisides and as additives, e.g. to printing ink. 3-aminopropane-1,2-diol or 1-aminopropane-2,3-diol, also known as iso-serinol, hereinafter denoted APD, and N-methyl-3-aminopropane-1,2-diol, hereinafter denoted MAPD, as well as higher N-alkyl-APD compounds, are well known chemical compounds that are useful in medicine and also as a starting materials or as intermediates in the preparation of several useful end products.
Examples of the use of APD and MAPD are as intermediates in the production of medical products. In particular, APD and MAPD are used in the production of triiodinated aryl X-ray contrast agents. Examples of such compounds are those sold under the trademarks Omnipaque, Imagopaque, Visipaque, Ultravist, Xenetix, and Oxilan.
For the use in medicine in particular, it is important to obtain end products in the form of Active Pharmaceutical Ingredients (API) with high purity, as required according to e.g. the US Pharmacopeia. The purity requirements are particularly important for X-ray contrast agents which are injected in large doses, up to 150 g in one single dose. In the preparation of the end products, it is therefore of crucial importance that also the intermediates used, such as APD and MAPD, are of high purity to avoid laborious and expensive purification procedures as much as possible. In order to be able to provide APD and MAPD with acceptable purity and to a competitive price, it is always important to strive to optimize the processes of manufacture to convert as much as possible of the starting material to the desired end product, and to avoid as much as possible the formation of side products, and in particular such products that are difficult or laborious to remove from the desired end product.
In the production of chemicals, it is further of great importance to endeavor to use processes and starting materials that are as efficient, cheap and safe as possible, in order to avoid exposure of the workers and the environment of potential hazards.
APD and N-alkyl-APD are frequently produced from 1-chloro-2,3-propanediol, hereinafter 1-CPD, by reaction with aqueous ammonia or alkylamine, see e.g. Rider, T. H. and Hill, A. J., Studies of Glycidol. II. Reactions with secondary amines, JACS, 1930, 52, 1528-1530, EP 0470004 B1 (Daicel) and U.S. Pat. No. 6,111,142 (Dibra S.p.a.) The reaction is known to be a two-step reaction. The first step is the formation of oxiranylmethanol (hereinafter denoted by its trivial name glycidol) from 1-CPD under alkaline conditions. The second step comprises an aminolysis reaction wherein the glycidol formed in the first step is reacted with ammonia ammonium, or with a solution of an alkylamine, preferably in aqueous solution.
Traditionally, the process is conducted in batch reactors with continuous vigorous stirring, usually in a one pot fashion. The overall reaction is slow and a number of impurities are formed, such as glycerol, serinol, bis- and tert. hydroxyalkyl amines and di-ethers. For use as intermediates, e.g. in pharmaceuticals, the APD or N-alkyl-APD must be further purified to an acceptable level of purity, see e.g. U.S. Pat. No. 6,111,142.
CN patent application no. 1012501 15 of Zhejiang University describes the production of APD from a premix of 1-CPD and excess ammonia in a tubular reactor heated to a constant temperature of 60 to 100° C.
Alternatively, APD and N-alkyl-APD could be produced directly from glycidol. Processes for the production of alpha amino alcohols, and in particular of APD and N-alkyl-APD, from glycidol and its derivatives by reaction with aqueous ammonia or alkylamines, are described in the prior art, see for example U.S. Pat. No. 4,360,697 and U.S. Pat. No. 4,358,615 (both of Degussa AG), EP 0364708 (Kali Chemie) and EP 0470004 (Daicel), and references listed therein.
However, at ambient temperature, glycidol of high purity is a slightly viscous liquid that is unstable and is not often encountered in pure form. The compound is an irritant of the skin, eyes, and mucous membranes and is toxic by inhalation. 1-CPD is also known to be toxic by inhalation and if swallowed, and is irritating to skin, eyes, mucous membranes.
Therefore, since glycidol in the sufficiently pure form which is required, in particular in the preparation of intermediates for API manufacture, is unstable, and both glycidol and 1-CPD are toxic, there remains a desire to reach to processes and production methods wherein the safety is improved, preferably without increasing the manufacturing costs considerably.